In about 1983, a surgical oncologist, E. W. Martin, Jr., M.D. and a physicist-electrical engineer, M. O. Thurston, Ph.D. combined their talents to explore then perceived deficiencies in the treatment of colorectal cancer. Why did it recur? Investigators then opined that some tumor was “missed” in surgery in that it was not located by pre-operational imaging, intra-operative visualization or palpation. Such hidden neoplastic tissue was referred to as “occult” tumor and was considered to be an important aspect of the recurrence of cancer and lessoning of patient survivability. The Martin-Thurston approach at that time was to radio-label an antibody specific to the tumor, inject it prior to surgery, then carry out surgery using current surgical protocols, whereupon a hand-held probe radiation detector was used intra-operatively to scan the surgical site for occult tumors. Early studies showed the necessity of delaying this surgery following the injection of locator or radiolabeled antibodies. That delay permitted the labeled antibody to preferentially concentrate at neoplastic tissue as well as to permit normal body function based reduction of background radiation. This procedure is described in U.S. Pat. No. 4,782,840 by Martin, Jr. and Thurston entitled “Method for Locating, Differentiating, and Removing Neoplasms”, issued Nov. 8, 1988. The procedure was referred to as “radio immunoguided surgery” or “RIGS®”.
The evolution of the hand-held probe and its associated control system was not a trivial endeavor, requiring extensive research. In this regard, the system was required to distinguish the totally random and spontaneous isotopic emissions of occult tumor from the same form of totally random isotopic background emissions. For a variety of important reasons, 125I was elected as the radioisotope label of choice, having a half-life of about sixty days. Concerning the randomness of an isotope, from a given point in time, an atom of 125I might emit a photon after five minutes from a starting point and another emission might occur a year later. The sixty day half-life is an average (the time required for the rate of such emissions to decrease to one half). A successful control approach for differentiating neoplastic tissue from background was statistically based upon count rate. The basis of that statistical control is described by Ramsey and Thurston in U.S. Pat. No. 4,889,991 entitled “Gamma Radiation Detector with Enhanced Signal Treatment”, issued Dec. 26, 1989.
Returning to the 125I radiolabel, studies carried out by Dr. Thurston showed that to accommodate the RIGS procedure with the necessary generally multi-week waiting period permitting body clearance of background radiation, a relatively longer half-life isotope having no high energy component and a dominant low energy was called for. 125I was essentially the only isotope with characteristics suitable for the RIGS procedure. However, both patients and health care personnel were not entirely receptive to working with or being injected with this radioactivity. While the sixty-day half-life of 125I fulfilled the waiting interval needs, it posed problems among others, with respect to regulatory agency requirements. Radioactive material, including anything contaminated with it must be protectively stored for a period amounting to ten times its half-life. Thus, for the case of 125I, the storage interval became six hundred days, a time element considered quite burdensome. Notwithstanding its lower energy characteristic (27 Kev) the emissions from this labeling isotope could inflict damage upon associated antibodies during shelf life. Thus, about one out of each six antibodies was labeled.
During the formative years of the RIGS system, the locators or antibodies, which were radiolabeled, were specific to the neoplasm or tumor itself. As these materials were improved, the locators developed were specific to tumor-associated cell surface antigens. The term “cell surface antigen” refers to an antigen of the plasma membrane proper and to any part of the tumor cell periphery, including the extracellular matrix. Most of the antigens demonstrated on the surface of cells have been chemically defined as polysaccharides, glycoproteins, glycolipids or proteins. A high molecular weight (200,000-400,000) tumor associated glycoprotein, called TAG-72, is present in 85% of colorectal cancers although there is considerable heterogeneity in its expression in the primary tumor, lymph nodes, and distant metastasizes. TAG-72 occurs widely on human carcinoma cells, including certain human breast carcinoma cell lines, but is absent in normal healthy adult tissues, except secretory-phase endometrium. One of the first antibodies of this type used with the RIGS system was called B72.3.
Colorectal adenocarcinomas have their genesis in mucin-secreting cells. Colon cancer occurs in the lining of the colon, which has to be coated at a rather high rate with mucin both for lubrication and digestive juice protection purposes. The epithelial cells involved reproduce at a very high rate. When such cells transform to cancer cells, they continue to secrete mucin but such mucin is distinctly different from mucin produced from non-malignant cells. It was found that TAG antibodies were capable of binding to these abnormal mucins called sialomucins, to locate or indicate the presence of cancer cells.
A variety of monoclonal antibodies reactive with human gastrointestinal carcinoma evolved. Of particular note, were the monoclonal antibodies (MAb) CC49 (ATCC CRL9459) and CC83 (ATCC CRL9453) developed by Schlom and coworkers at the National Cancer Institute. These antibodies exhibit increased reactivity to antigen-positive tissue, reflecting a higher affinity. See U.S. Pat. No. 5,512,443.
Essentially, hundreds of surgical procedures were carried out by surgeons employing the RIGS system in conjunction with sialomucin binding locators, such as CC49 and CC83. During this period E. W. Martin, Jr. and associating surgeons detected “probe positive” (locator bound sialomucin) lymph nodes. It may be recalled that the locators are specific to a by-product of tumor as opposed to tumor itself. Generally, these lymph nodes were readily accessible with the RIGS probe, being present along, for example, the aorta, vena cava or near the liver. Notwithstanding the controversy necessarily involved in removing lymph structure, these probe-positive lymph nodes were directed to pathology along with the resected tumor burden. The generally received response was that the dissected nodes were hyperactive but no presence of cancer cells was detected. The issue as to the appropriateness of removing these probe-positive lymph nodes remained essentially unresolved until patient survival data was evolved. Data collected with respect to patients having had probe-positive lymph nodes removed indicated what has been called “remarkable” survival improvement. An analysis was subsequently carried out with respect to the question as to whether a small number of malignant cells in a lymph node would be readily detected by frozen section techniques. Assuming a spherical node of 0.5 cm diameter, an examination of the entire node in six-micron sections would require over 800 sections with a total area of 1600 cm2. The likelihood of observing malignant cells would have been, at best, remote. See the following publication:    1. Barbera-Guillen, et al., “First Results for Resetting the Anti-Tumor Immune Response by Immune Corrective Surgery in Colon Cancer” Am. J. Surg, 1998,176:339-343.
In the early 1990s investigators utilized the RIGS system to locate, differentiate and stage other types of cancer, for instance, endocrine tumors involved, inter alia, with breast, children, gastrinomas, lung and nervous system. Generally, the approach was to administer a radiolabeled somatostatin congener to assess the patient with the RIGS probe. However, before subjecting the patient to such administration, an initial determination preferably was made as to whether the radiolabeled somatostatin congener would bind to the tumor site, i.e., whether somatostatin receptors are associated with the neoplastic tissue. This was conveniently done with a wide variety of endocrine tumors, which release peptides or hormones, referred to as “biochemical markers.” In order to make this determination, initially a biochemical marker-inhibiting dose of unlabeled somatastatin congener was administered to the patient. The biochemical marker associated with the neoplastic tissue then was monitored to determine whether the administered somatostatin congener reduces the presence of the marker in the patient. If the monitored presence of the marker was reduced, then the surgeon could be confident that the neoplastic tissue or tumor contains receptors to which the somatostatin would bind. Thus, the administration of radiolabeled somatostatin congener was appropriate for such patient. If the biochemical marker associated with the neoplastic tissue was not appropriately reduced following the administration of the unlabeled somatostatin congener, then the neoplastic tissue may not be determinable by the use of radiolabeled somatostatin congener and alternative modalities of treatment would be considered, such as the use of radiolabeled antibodies.
See: O'Dorisio, et al., U.S. Pat. No. 5,590,656; entitled “Application of Peptide/Cell Receptor Kinetics Utilizing Radiolabeled Somatostatin Congeners in the In Situ, In Vivo Detection and Differentiation of Neoplastic Tissue”; issued Jan. 7, 1997 and incorporated herein by reference.
For a variety of reasons, the use of the RIGS system was suspended and oncologists have no technique available for detecting cancer inducing lymph nodes. In consequence, the survival rates for patients having undergone tumor-burden removal associated with colonic cancers have generally descended to pre-RIGS levels.